ACAT inhibitor HL-004 accelerates the regression of hypercholesterolemia in stroke-prone spontaneously hypertensive rats (SHRSP): stimulation of bile acid production by HL-004

The effect of the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor HL-004 on bile acid production was studied during the regression phase of pre-establised hypercholesterolemia in stroke-prone spontaneously hypertensive rats (SHRSP). These rats were fed a hypercholesterolemic diet containing 5% cholesterol, 2% cholic acid, and 20% suet for 30 days to induce hypercholesterolemia. The regression phase was started by switching the diet to normal chow, followed by another 30 days of the diet. The decrease in serum cholesterol level was accelerated by treatment with 0.09% HL-004. At the end of regression, hepatic ACAT activity was significantly lower in the HL-004 treated animals, an event concomitant with the significant decrease in cholesteryl ester content in the liver. In contrast hepatic cholesterol 7α-hydroxylase activity was maintained at a higher level in the HL-004 treated animals. HL-004 increased the secretion of bile acid and biliary lipids in bile duct-cannulated SHRSP. In HepG2 cells, HL-004 at 1–30 μM dose-dependently stimulated bile acid synthesis from [3H]cholesterol. When cholesterol 7α-hydroxylase activity of the liver was compared ex vivo in the presence and in the absence of exogenous cholesterol, it was suggested that the higher 7α-hydroxylase acitivy of the HL-004 group could be attributed not only to expansion of the endogenous cholesterol pool, which may be the result of hepatic ACAT inhibition by HL-004 but to the direct effect of HL-004 on bile acid production. Thus, HL-004 accelerates the regression of hypercholesterolemia, an event which may be related to the stimulation of bile acid production in the liver.